The burden of comedication among patients with inflammatory bowel disease.

ORIGINAL ARTICLE

The Burden of Comedication Among Patients with Inflammatory Bowel Disease Jessie P. Buckley, MPH,* ,† Michael D. Kappelman, MD, MPH,‡ Jeffery K. Allen, MS,† Susan A. Van Meter, MD,§ and Suzanne F. Cook, PhD†

Background: Polypharmacy is of growing concern in the chronically ill, including individuals with inflammatory bowel disease (IBD). The authors aimed to describe the prevalence and predictors of non-IBD medication use and to compare drug use among individuals with and without IBD. Methods: This cross-sectional study included members of health plans included in the Thomson Reuters MarketScan databases with continuous enrollment during 2009 and 2010. Patients with IBD were identified through diagnosis codes and IBD medication dispensings and matched to 5 individuals without IBD. The prevalences of dispensed prescriptions for analgesics (narcotics, nonnarcotics), psychiatric medications (anxiolytics/ sedatives/hypnotics, antidepressants), and broad drug classes defined by the Anatomic Therapeutic Classification system were estimated. Predictors of non-IBD medication use and comparisons of drug use by IBD status were evaluated using logistic regression. Results: The prevalence of medication use was higher among patients with IBD than matched members of the general population for nearly every drug class examined, including narcotic analgesics (48.1% versus 34.1%), nonnarcotic analgesics (12.8% versus 8.1%), anxiolytics/sedatives/hypnotics (25.8% versus 16.7%), and antidepressants (28.3% versus 19.4%). Medicaid insurance, middle age, gastrointestinal surgery, Crohn’s disease, and increasing number of inpatient, and outpatient, and prescription events were significantly associated with analgesic and psychiatric medication use among patients with IBD. Psychiatric drug dispensings were more common among female IBD patients than male patients.

Conclusions: Patients with IBD have increased medication use, particularly of analgesic and psychiatric drugs. IBD care providers should be aware of polypharmacy and its potential for drug interactions. (Inflamm Bowel Dis 2013;19:2725–2736) Key Words: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, comedication, polypharmacy

I

nflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are immune-mediated illnesses characterized by chronic inflammation of the gastrointestinal (GI) tract. IBD is estimated to affect 1.4 million Americans and is associated with substantial morbidity and decreased quality of life.1–4 Because IBD is a life-long condition, the goals of treatment are to induce remission of acute flares, maintain remission, Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.ibdjournal.org). Received for publication August 5, 2013; Accepted September 11, 2013. From the *Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; †Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, North Carolina; ‡Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and §Neurosciences Therapy Area, GlaxoSmithKline, Research Triangle Park, North Carolina. Supported by GlaxoSmithKline. S. F. Cook, J. K. Allen, and S. A. Van Meter are employees of GlaxoSmithKline. J. P. Buckley received funding through a research assistantship at GlaxoSmithKline. M. D. Kappelman is a consultant to GlaxoSmithKline and has received research support from Janssen Biotech. Reprints: Jessie P. Buckley, MPH, Department of Epidemiology, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC 27599-7435 (e-mail: [email protected]). Copyright © 2013 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/01.MIB.0000435442.07237.a4 Published online 7 November 2013.

Inflamm Bowel Dis Volume 19, Number 13, December 2013

and improve quality of life. A primary means of achieving these goals is through pharmacotherapy. IBD is a complex disease that may require numerous medications to treat symptoms and maintain remission. In addition, individuals with IBD may take medications to treat common sequelae such as chronic pain and psychiatric comorbidity. Sleep problems, anxiety, and depression are common among patients with IBD5–9 and there is a high prevalence of narcotic use to treat chronic pain.10–12 Furthermore, patients with IBD may be prescribed medications to manage comorbid chronic conditions that are common in the general population (e.g., diabetes and heart disease) or for which they are at increased risk (e.g., colorectal cancer, immune-mediated diseases, thromboembolism).13–19 Complicated IBD treatment regimes and comedication for disease sequelae and comorbid conditions have been shown to result in substantial polypharmacy in the IBD population.20,21 Polypharmacy is of growing concern in the chronically ill as it is associated with adverse drug–drug interactions, reduced prescription therapy compliance, and higher medical costs.22,23 In IBD, many medications commonly used to treat disease symptoms and comorbidities have potential for adverse drug interactions when used in combination.24 Polypharmacy has also been correlated with increased disease activity and decreased quality of life in patients with IBD.20 www.ibdjournal.org |

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Copyright © 2013 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.


Buckley et al

Although the prevalence of comorbidity among patients with IBD has been described, no previous reports have characterized the use of non-IBD medications in this population. The aims of this cross-sectional study were to (1) characterize the prevalence and predictors of non-IBD medication use among patients with IBD and (2) compare non-IBD prescription drug use among patients with IBD with that of the general population without IBD.

MATERIALS AND METHODS Study Design and Data Source This cross-sectional study used administrative claims data contained in the Thomson Reuters MarketScan Commercial Claims and Encounters, Medicare Supplemental, and Multi-State Medicaid Research Databases. These proprietary databases contain insurance claims on nearly 150 million individuals, including longitudinal data on inpatient and outpatient diagnoses and procedures linked to demographic characteristics, enrollment details, and prescription claims records. The MarketScan databases have been used widely for health research, including studies of IBD.9,16,25,26 The Commercial Database includes members of the working population younger than 65 years and their dependents who have employer-sponsored health insurance coverage from 1 of over 100 employer-sponsored and private health plans. The Medicare Supplemental Database includes Medicare beneficiaries with comprehensive employer-sponsored supplemental coverage. The Multi-State Medicaid Database includes Medicaid enrollees from 10 to 13 geographically dispersed states.

Sample Populations Individuals with claims in the Commercial and Medicare Supplemental databases were combined for analysis as these data sources include individuals with health insurance or supplemental coverage provided by the same group of employers. Analyses were conducted separately in the Medicaid population. The source populations included all patients in the MarketScan databases with continuous health plan enrollment and pharmacy benefits during January 1, 2009, to December 31, 2010. Prevalent patients with IBD were identified using an adaptation of a validated IBD case definition that has been used in previous studies.27–31 Patients were classified as having IBD if they satisfied either of the following conditions: (1) 3 or more healthcare contacts for CD or UC (ICD-9CM codes 555.xx and 556.xx, respectively) on separate days or (2) at least 1 healthcare contact for CD or UC and at least 1 pharmacy claim for any of the following medications: mesalamine, olsalazine, balsalazide, sulfasalazine, 6-mercaptopurine (6-MP), azathioprine, methotrexate, enteral budesonide, or biologics (infliximab, adalimumab, certolizumab, or natalizumab). IBD type was classified as CD or UC based on the majority of the last 9 claims; otherwise, the patient was classified as indeterminate IBD. At the time each IBD patient entered the study population, he or she was matched to 5 randomly sampled members of the study population without

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IBD. Matching was on age, gender, and region in the Commercial and Medicare Supplemental population and on age and gender in the Multi-State Medicaid population.

Comedication Outcomes Non-IBD prescription drug use was ascertained from claims for dispensed prescriptions in the MarketScan databases. Medications that are coded using the National Drug Code system were mapped to European Pharmaceutical Market Research Association (EphMRA) and the Pharmaceutical Business Intelligence and Research Group (PBIRG) Anatomical Classification System drug classes. The EphMRA/PBIRG Anatomical Classification System groups pharmaceutical products based on their anatomical site of action, indication, or composition. Prescription dispensings were assessed at both the Anatomical Classification System main group (16 classes) and the 3-digit levels (100 classes) for analysis. We also assessed the following 4 drug classes of a priori interest using 5-digit Anatomical Classification System codes: narcotic analgesics, nonnarcotic analgesics, anxiolytics/sedatives/ hypnotics, and antidepressants. Hydroxyzine was excluded from the anxiolytics/sedatives/hypnotics group because it is not primarily used for these indications. Clomipramine and alprazolam are classified as antidepressants by the Anatomical Classification System but were instead included as anxiolytics/sedatives/hypnotics because they are primarily used to treat anxiety disorders. Generic drugs included in each of the a priori classes are listed in the Appendix. IBD medications were excluded from all comedication definitions. In addition, laxatives were excluded from the list of the 10 most common 3-digit Anatomical Classification System classes because they are used to prepare patients for GI procedures. To identify patients with repeated drug use, multiple prescriptions were defined as at least 3 claims for a single medication in a drug class (does not include single prescription for multiple drugs in a class).

Covariates of Interest Demographic information included age and gender. Region (Northeast, North Central, South, or West) was available for the Commercial and Medicare Supplemental cohort, but not the Medicaid cohort. Markers of healthcare utilization included the number of inpatient and outpatient contacts and the number of unique generic medications dispensed during the 2-year study period. Additional predictors of interest for analyses within the IBD population included GI surgery, IBD medication use, and comorbid conditions. GI surgeries were defined using the following CPT-4 codes: 43020–43135, 43280–44346, 44500–45190, 45395–46505, 46700–46999, and 49000–49999; endoscopy or surgery of oral cavity and liver, biliary tract, and pancreas were excluded as we were interested in luminal GI procedures. IBD medications included oral steroids, oral and rectal aminosalicylates (5-aminosalicylic acid, including mesalamine, olsalazine, balsalazide, and sulfasalazine), 6-MP or azathioprine, rectal steroids (enema, suppository, and foam), methotrexate, cyclosporine or tacrolimus, and biologics (infliximab, adalimumab, certolizumab, or natalizumab).

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Comorbidities were characterized using the Elixhauser index, a set of 30 comorbidity categories associated with length of stay, hospital charges, and in-hospital death in a hospitalized population.32 This algorithm has been validated among patients with IBD.33 As our study population was not restricted to hospitalized patients, we used the ICD-9-CM diagnosis codes to identify individual comorbidities from all encounters (inpatient and outpatient diagnoses). We also examined comorbid conditions associated with IBD as defined in a previous study of IBD comorbidity (ankylosing spondylitis, asthma, colon cancer, ischemic stroke, multiple sclerosis, ischemic heart disease, primary sclerosing cholangitis, rheumatoid arthritis, and thrombosis or embolism).34 Final models included comorbidities that were 3 or more times as common among individuals with IBD as those without in either the Commercial and Medicare Supplemental cohort or the Multi-State Medicaid cohort.

Statistical Analyses Crude bivariate analyses were conducted using chi-square tests. Prevalence odds ratios (POR) and 95% confidence intervals comparing the prevalence of dispensed prescriptions for analgesic, psychiatric, and Anatomical Classification System drug classes among those with and without IBD were estimated using logistic regression. Models were not adjusted for markers of healthcare utilization because they are characteristics of the IBD population that mediate the need for patients to be treated with prescription medications. PORs were generated for any dispensed prescription and for multiple prescriptions. Predictors of medication use among patients with IBD were examined in multivariate logistic regression models for the analgesic and psychiatric drug classes of interest. Variables assessed included age, gender, region, IBD type, comorbidities, markers of healthcare utilization, GI surgery, and IBD medication use. Analyses were performed among the total IBD population and with stratification by IBD type. All analyses were conducted separately for the Commercial and Medicare Supplemental population and the Multi-State Medicaid population. Data analysis was performed in SAS v.9.2 (SAS Institute, Cary, NC).

Ethical Considerations This study is not considered as human subjects’ research because it has used previously existing deidentified data.

RESULTS Commercial and Medicare Supplemental Population Of the 25,538,901 individuals with continuous health plan enrollment and pharmacy benefits during 2009 and 2010 in the Commercial and Medicare Supplemental databases, 104,582 were identified as having IBD (Fig. 1). IBD prevalence increased with age until 50 to 59 years and there was a slight predominance of females (Table 1). Individuals with IBD had a high prevalence of prescription drug use during the study period; over half had

Burden of Comedication Among Patients with IBD

dispensed prescriptions for 10 or more unique generic compounds. Compared with age-, gender-, and region-matched members of the general population, individuals with IBD had more inpatient, outpatient, and prescription events and a higher prevalence of GI surgery, IBD mediation use, and the comorbidities listed in Table 1 (P , 0.0001 for all characteristics). The most common drug classes dispensed to individuals with and without IBD are reported in Table 2. Although the top ranked drug classes were similar between patients with IBD and the general population, the prevalence of drug use was generally higher in the IBD group. For example, analgesics were the second most commonly prescribed drug class among persons with and without IBD but the prevalence of an analgesic prescription was 14.2% higher among individuals with IBD. Analgesic and psychiatric drug use was common among patients with IBD. Nearly half of patients with IBD were dispensed a narcotic analgesic during the study period and 20% had 3 or more narcotic analgesic prescriptions. The prevalence of prescriptions for all 4 drugs groups was higher among individuals with CD than those with UC: narcotic analgesics, 52.5% versus 44.4%; nonnarcotic analgesics, 14.2% versus 11.5%; anxiolytics/ sedatives/hypnotics, 27.2% versus 24.6%; and antidepressants, 30.4% versus 26.5% (P , 0.001 for all comparisons). PORs comparing the prevalence of any and multiple dispensed prescriptions among those with IBD to those without IBD are presented in Table 3. The prevalence of all 4 analgesic and psychiatric drug classes was significantly elevated among those with IBD. The strength of these associations was similar for any and multiple use. PORs were also significantly higher among individuals with IBD for all 16 of the Anatomic Classification System main groups with PORs for any use ranging between 1.13 and 5.58. The strongest associations were observed for alimentary tract and metabolism (POR, 5.58; 95% confidence interval, 5.49– 5.67) and blood and blood forming organs (POR, 2.71; 95% confidence interval, 2.66–2.77). When stratified by IBD type, associations were stronger among individuals with CD than those with UC (data not shown). Independent predictors of narcotic and psychiatric drug use among patients with IBD are reported in Table 4. Age was significantly associated with the use of analgesic and psychiatric medications; children had the lowest prevalence of dispensed prescriptions for all the drug classes. The adjusted prevalence odds of nonnarcotic analgesic and psychiatric medication use was higher among female patients, whereas the prevalence odds of narcotic use was higher among male patients. There were few associations between comorbidities and prevalence of drug use; there was a positive relationship between rheumatoid arthritis and analgesic use and an inverse relationship between primary sclerosing cholangitis and analgesic and psychiatric medications. Healthcare utilization was strongly associated with the use of narcotic and psychiatric drug use among patients with IBD. Adjusted PORs for drug use increased with increasing number of inpatient visits, outpatient visits, and unique generic prescriptions. This trend was the strongest for prescription events; the www.ibdjournal.org |

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FIGURE 1. Study population diagram for a cross-sectional administrative claims study of comedication in patients with IBD.

prevalence odds of drug use was over 30 times higher among patients with IBD with $20 prescriptions than among those with 0 to 4 unique generic prescriptions for all classes examined. GI surgery during the study period was associated with over twice the prevalence odds of taking a narcotic analgesic. Use of the IBD medications 5-aminosalicylic acid, azathioprine/6-MP, rectal steroids, methotrexate, and cyclosporine or tacrolimus were generally inversely associated with prescriptions for analgesic and psychiatric medications.

Multi-State Medicaid Population In the Multi-State Medicaid population, 2777 of 1,934,298 eligible individuals met the IBD case definition (Fig. 1). Compared with the Commercial and Medicare Supplemental cohort, the Medicaid IBD population had a higher proportion of female patients and a younger age distribution (see Table, Supplement Digital Content 1, http://links.lww.com/IBD/A330). In addition, comorbidities, healthcare utilization, and medication use were more common among Medicaid recipients regardless of the status of IBD (see Tables, Supplement Digital Content 1, http://links.lww.com/IBD/A330 and Supplement Digital Content 2, http://links.lww.com/IBD/A331). Analgesic and psychiatric medication use was very common among patients with IBD insured by Medicaid: narcotic analgesics (73%), nonnarcotic analgesics (40%), anxiolytics/sedatives/hypnotics (42%), and antidepressants (52%). Although drug use was more common in the Medicaid population, patterns of association comparing prevalence of drug use among those with and without IBD were similar to the Commercial and Medicare Supplemental results. Patients with IBD had significantly higher prevalence odds of medication use for nearly every drug class examined (see Table, Supplement

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Digital Content 3, http://links.lww.com/IBD/A332). Independent predictors of analgesic and psychiatric medication use among patients with IBD were also similar to those identified in the Commercial and Medicare Supplemental cohort (see Table, Supplement Digital Content 4, http://links.lww.com/IBD/A333).

DISCUSSION In this study, we observed that patients with IBD have substantial use of medications prescribed for reasons other than treatment and control of IBD. For every broad drug class examined, the prevalence of drug use was higher among patients with IBD than matched members of the general population. Prescriptions for analgesic and psychiatric medications were particularly common among patients with IBD, especially those receiving Medicaid. This degree of polypharmacy is an important aspect of disease burden that has not been previously described. Furthermore, polypharmacy has important clinical implications, including the impact on medication adherence and the potential for drug–drug interactions. Although there is little literature on non-IBD medication use, previous studies investigating polypharmacy among patients with IBD indicate that medication use is high. A study of 393 geriatric patients with IBD reported major polypharmacy (defined as $5 medications) in 22% of patients.21 In a study of 291 patients with CD, Cross et al20 reported that half had major polypharmacy at their initial visit to a tertiary referral center and polypharmacy was independently associated with age (.40 years), duration of disease, and female sex. By examining broad drug classes in addition to specific medications, this study is the





TABLE 1. Characteristics of Patients with IBD and Matched Members of the General Population, Commercial and Medicare Supplemental MarketScan Databases, 2009 and 2010 Total IBD Characteristic Total (N) Age (yr) 0–9 10–19 20–29 30–39 40–49 50–59 60–69 $70 Gender Male Female Region Northeast North central South West Unknown Comorbidities Liver disease Chronic peptic ulcer Weight loss Fluid and electrolyte disorders Blood loss anemia Deficiency anemias Ankylosing spondylitis Colon cancer Primary sclerosing cholangitis Rheumatoid arthritis Inpatient visits 0 1–3 $4 Outpatient visits 0–9 10–29 $30 Unique generic prescriptions 0–4 5–9 10–19 $20 GI surgery Yes

n

CD %

104,582

n

General Populationa

UC %

47,927

n

%

55,422

n

%

522,910

639 5681 10,527 16,528 21,425 24,540 15,965 9277

0.6 5.4 10.1 15.8 20.5 23.5 15.3 8.9

355 3533 5538 7855 9541 10,675 6977 3453

0.7 7.4 11.6 16.4 19.9 22.3 14.6 7.2

278 2091 4872 8486 11,642 13,571 8767 5715

0.5 3.8 8.8 15.3 21.0 24.5 15.8 10.3

3195 28,405 52,635 82,640 107,125 122,700 79,825 46,385

0.6 5.4 10.1 15.8 20.5 23.5 15.3 8.9

48,114 56,468

46.0 54.0

21,252 26,675

44.3 55.7

26,276 29,146

47.4 52.6

240,570 282,340

46.0 54.0

15,462 32,708 39,812 16,432 168

14.8 31.3 38.1 15.7 0.2

6966 15,712 18,513 6654 82

14.5 32.8 38.6 13.9 0.2

8275 16,616 20,837 9610 84

14.9 30.0 37.6 17.3 0.2

77,310 163,540 199,060 82,160 840

14.8 31.3 38.1 15.7 0.2

4818 285 6656 13,118 3001 22,164 849 836 1119 4248

4.6 0.3 6.4 12.5 2.9 21.2 0.8 0.8 1.1 4.1

2446 184 3703 6734 1501 11,901 515 376 276 2289

5.1 0.4 7.7 14.1 3.1 24.8 1.1 0.8 0.6 4.8

2316 95 2887 6272 1470 10,015 324 446 834 1910

4.2 0.2 5.2 11.3 2.7 18.1 0.6 0.8 1.5 3.4

6675 287 6406 18,152 2860 35,211 359 1623 138 6929

1.3 0.1 1.2 3.5 0.5 6.7 0.1 0.3 0.0 1.3

75,450 26,701 2431

72.1 25.5 2.3

32,846 13,770 1311

68.5 28.7 2.7

41,624 12,692 1106

75.1 22.9 2.0

467,414 53,779 1717

89.4 10.3 0.3

15,193 46,269 43,120

14.5 44.2 41.2

5899 20,530 21,498

12.3 42.8 44.9

9088 25,179 21,155

16.4 45.4 38.2

218,112 194,673 110,125

41.7 37.2 21.1

16,877 30,866 39,757 17,082

16.1 29.5 38.0 16.3

7377 13,478 18,402 8670

15.4 28.1 38.4 18.1

9314 17,008 20,886 8214

16.8 30.7 37.7 14.8

224,464 151,916 117,716 28,814

42.9 29.1 22.5 5.5

96,544

92.3

43,179

90.1

52,177

94.1

517,430

99.0

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Buckley et al

TABLE 1 (Continued) Total IBD Characteristic IBD medication use Oral steroid 5-Aminosalicylic acid drugs Azathioprine/6-MP Rectal steroid Methotrexate Cyclosporine or tacrolimus Biologics

CD

General Populationa

UC

n

%

n

%

n

%

n

%

41,714 76,288 22,064 1648 2343 556 15,245

39.9 72.9 21.1 1.6 2.2 0.5 14.6

19,361 28,605 13,256 242 1527 197 11,560

40.4 59.7 27.7 0.5 3.2 0.4 24.1

21,941 46,608 8642 1390 787 356 3619

39.6 84.1 15.6 2.5 1.4 0.6 6.5

92,729 1404 579 35 2875 665 1190

17.7 0.3 0.1 0.0 0.6 0.1 0.2

a

Matched to total IBD population on age, gender, and region.

first to provide an integrated picture of prescription medication use among patients with IBD. Our findings, in a more generalizable population, reinforce the observations of these earlier, smaller studies, indicating that polypharmacy is an important issue facing patients with IBD and their providers. The most common broad classes of non-IBD drugs prescribed to patients with IBD were systemic antibacterials, analgesics, antacids, antiflatulents and antiulcerants, psychoanaleptics, and psycholeptics. Although these were also the most common classes prescribed in the general population, patients with IBD had a higher prevalence of drug use for all classes. A retrospective study of 291 patients with CD at a tertiary

referral center reported that the most commonly used medications were IBD drugs, vitamins and minerals, nonnarcotic analgesics, and GI symptomatic drugs.20 Although we could not ascertain vitamin and mineral use using claims data, both studies indicate that analgesics are commonly used by patients with IBD. We observed a significantly higher prevalence of both narcotic and nonnarcotic analgesic use among individuals with IBD compared with the general population. Narcotic use was particularly common, with 48% and 73% of patients with IBD in the Commercial/Medicare and the Medicaid population having at least 1 narcotic prescription, respectively. Independent predictors

TABLE 2. Ten Most Common 3-Digit Anatomical Classification System Drug Classesa Among Patients with IBD Compared with the General Population, Commercial, and Medicare Supplemental MarketScan Databases, 2009 and 2010 Rank 1 2 3 4 5 6 7 8 9 10

IBD Population Drug Class

n

Systemic antibacterials Analgesics Antacids, antiflatulents, and anti-ulcerants Psychoanaleptics Psycholeptics Lipid-regulating/anti-atheroma preparations Agents acting on the renin–angiotensin system Topical corticosteroids Anti-inflammatory and antirheumatic products Gynecological anti-infectives

74,555 54,426 35,169 30,634 29,595 27,749 22,648 22,486 22,282 21,995

%

General Populationb Drug Class

n

%

71.3 52.0 33.6 29.3 28.3 26.5 21.7 21.5 21.3 21.0

Systemic antibacterials Analgesic Lipid-regulating/anti-atheroma preparations Anti-inflammatory and anti-rheumatic products Agents acting on the renin–angiotensin system Psychoanaleptics Psycholeptics Nasal preparations Antacids, antiflatulents, and anti-ulcerants Cough and cold preparations

309,873 197,420 122,480 121,682 111,947 107,741 98,010 91,483 90,300 79,984

59.3 37.8 23.4 23.3 21.4 20.6 18.7 17.5 17.3 15.3

a IBD medications excluded from drug class definitions: oral steroids, oral and rectal aminosalicylates (5-aminosalicylic acid, including mesalamine, olsalazine, balsalazide, sulfasalazine), 6-MP or azathioprine, rectal steroids (enema, suppository, foam), methotrexate, cyclosporine or tacrolimus, and biologics (infliximab, adalimumab, certolizumab, or natalizumab). b Matched to total IBD population on age, gender, and region.

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TABLE 3. PORs and 95% Confidence Interval Comparing Use of A Priori and Anatomical Classification System Main Group Drug Classesa Among Patients with IBD to the General Population,b Commercial and Medicare Supplemental MarketScan Databases, 2009 and 2010 Multiple Prescriptionsc

Any Prescription Prescription Drug Class A priori drug classes Narcotic analgesics Non-narcotic analgesics Anxiolytics/sedatives/hypnotics Antidepressants Anatomical Classification System main groups Alimentary tract and metabolism Blood and blood forming organs Cardiovascular system Dermatologicals Genito-urinary system and sex hormones Systemic hormonal preparations General anti-infectives, systemic Hospital solutions Antineoplastic and immunomodulating agents Musculo-skeletal system Nervous system Parasitology Respiratory system Sensory organs Diagnostic agents Various

n

%

POR (95% CI)

50,330 13,359 26,969 29,596

48.1 12.8 25.8 28.3

1.81 1.68 1.77 1.67

78,108 16,270 51,506 35,599 46,562 12,578 78,097 35 3584 36,994 70,003 2524 47,026 20,285 4934 5750

74.7 15.6 49.3 34.0 44.5 12.0 74.7 0.0 3.4 35.4 66.9 2.4 45.0 19.4 4.7 5.5

5.58 2.71 1.52 1.68 2.11 1.13 1.80 2.57 1.65 1.20 1.87 1.63 1.40 1.32 1.18 1.64

n

%

POR (95% CI)

(1.79–1.84) (1.65–1.72) (1.74–1.80) (1.64–1.70)

20,437 4159 14,898 23,362

19.5 4.0 14.3 22.3

2.37 2.08 1.90 1.63

(2.32–2.41) (2.01–2.16) (1.86–1.94) (1.61–1.66)

(5.49–5.67) (2.66–2.77) (1.50–1.56) (1.65–1.70) (2.08–2.14) (1.11–1.16) (1.78–1.83) (1.71–3.87) (1.58–1.71) (1.18–1.22) (1.85–1.90) (1.56–1.70) (1.38–1.42) (1.30–1.35) (1.14–1.22) (1.59–1.69)

42,372 11,723 41,127 7225 24,975 10,126 21,407 5 1805 15,998 44,016 694 17,771 3896 2488 2232

40.5 11.2 39.3 6.9 23.9 9.7 20.5 0.0 1.7 15.3 42.1 0.7 17.0 3.7 2.4 2.1

2.74 2.67 1.27 1.69 1.52 1.10 1.71 1.09 1.51 1.41 1.88 1.91 1.44 1.42 1.16 1.40

(2.70–2.78) (2.60–2.73) (1.25–1.29) (1.64–1.73) (1.50–1.55) (1.07–1.12) (1.68–1.74) (0.41–2.86) (1.44–1.60) (1.38–1.44) (1.85–1.90) (1.75–2.08) (1.42–1.47) (1.37–1.48) (1.11–1.21) (1.33–1.46)

a IBD medications excluded from drug class definitions: oral steroids, oral and rectal aminosalicylates (5-aminosalicylic acid, including mesalamine, olsalazine, balsalazide, sulfasalazine), 6-MP or azathioprine, rectal steroids (enema, suppository, foam), methotrexate, cyclosporine or tacrolimus, and biologics (infliximab, adalimumab, certolizumab, or natalizumab). b Matched to total IBD population on age, gender, and region. c Multiple is defined as 3 or more prescriptions for at least 1 drug in a drug class (does not include single prescriptions for 3 or more different drugs within a class). CI, confidence interval.

of analgesic use in both the populations include middle age, CD, GI surgery, and increasing number of inpatient, outpatient, and prescription events. Previous studies also reported associations with IBD-related surgery and polypharmacy and identified additional predictors of narcotic use among patients with IBD, including increased pain, more symptoms, worse disease activity, and smoking.10,11 Although clinical data were not available for assessment in our study, these previous findings are consistent with our observation of increased narcotic use with increased healthcare utilization, a marker of disease severity. Associations between narcotic use and worsened disease activity, quality of life, and adherence to medical treatment indicate that narcotic use may be an indicator of poor disease control. Use of anxiolytics/sedatives/hypnotics and antidepressants were more common in the IBD group than in the general population. Several previous studies have reported increases in psychiatric conditions among patients with IBD, including sleep

disturbance, anxiety, and depression.5–9 Presence of these conditions among patients with IBD have been associated with worse disease activity and reduced health-related quality of life.5,7,35 Interestingly, several studies have reported associations between narcotic and psychiatric drug use among patients with IBD.10,11,36 We identified several independent predictors of analgesic and psychiatric medication use. As has been reported in previous studies of IBD, prescriptions for nonnarcotic analgesic and psychiatric medications were more prevalent among female patients.11,20 Middle-age patients had a higher prevalence of all 4 a priori drug classes. This observation may be related to higher incidence of symptoms in this age group or to physician discomfort in prescribing medications to young and elderly patients and merits further exploration. As expected, markers of healthcare utilization, including the number of inpatient, outpatient, and prescription events, were associated with an increase in a priori drug use. Associations between IBD medications and prescription www.ibdjournal.org |

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TABLE 4. PORs and 95% CIa for Independent Predictors of A Priori Drug Use Among Patients with IBD, Commercial and Medicare Supplemental MarketScan Databases, 2009 and 2010 Characteristic Age (yr) 0–9 10–19 20–29 30–39 40–49 50–59 60–69 $70 Gender Female Male Region Northeast North central South West Unknown IBD type CD UC Indeterminate IBD Comorbidities Liver disease Chronic peptic ulcer Weight loss Fluid and electrolyte disorders Blood loss anemia Deficiency anemias Ankylosing spondylitis Colon cancer Primary sclerosing cholangitis Rheumatoid arthritis Inpatient visits 0 1–3 $4 Outpatient visits 0–9 10–29 $30 Unique generic prescriptions 0–4 5–9 10–19 $20

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Narcotic Analgesics

Nonnarcotic Analgesics

Anxiolytics/Sedatives/Hypnotics

Antidepressants

0.12 (0.09–0.15) 0.57 (0.52–0.61) 1 1.03 (0.97–1.09) 0.97 (0.91–1.02) 0.85 (0.80–0.89) 0.67 (0.63–0.71) 0.45 (0.42–0.48)

0.11 (0.06–0.23) 0.54 (0.47–0.62) 1 1.10 (1.02–1.19) 1.01 (0.93–1.09) 0.88 (0.82–0.95) 0.71 (0.66–0.77) 0.66 (0.61–0.73)

0.15 (0.09–0.24) 0.37 (0.33–0.42) 1 1.37 (1.28–1.47) 1.62 (1.52–1.73) 1.52 (1.43–1.63) 1.26 (1.18–1.35) 1.01 (0.93–1.08)

0.08 (0.05–0.14) 0.65 (0.59–0.72) 1 1.19 (1.12–1.27) 1.32 (1.24–1.40) 1.23 (1.16–1.31) 0.95 (0.89–1.01) 0.71 (0.66–0.77)

1 1.18 (1.15–1.22)

1 0.81 (0.78–0.84)

1 0.81 (0.78–0.84)

1 0.58 (0.56–0.60)

0.69 (0.66–0.72) 0.93 (0.90–0.97) 1 1.15 (1.10–1.20) 0.91 (0.63–1.32)

0.71 (0.66–0.76) 0.96 (0.91–1.00) 1 0.66 (0.62–0.70) 1.62 (1.05–2.51)

1.09 (1.04–1.15) 0.99 (0.95–1.02) 1 1.24 (1.18–1.29) 1.02 (0.68–1.54)

0.94 (0.89–0.98) 1.17 (1.13–1.22) 1 1.11 (1.06–1.17) 1.01 (0.68–1.50)

1 0.83 (0.81–0.86) 0.84 (0.74–0.96)

1 0.91 (0.88–0.95) 0.85 (0.71–1.03)

1 0.96 (0.93–0.99) 0.98 (0.85–1.13)

1 0.93 (0.90–0.96) 0.91 (0.79–1.05)

1.14 1.07 0.90 0.92 0.94 0.89 1.08 1.02 0.67 1.32

1.02 1.15 1.01 0.98 0.97 1.01 1.54 0.72 0.86 1.46

0.94 1.32 1.11 1.11 0.90 0.96 1.11 0.95 0.78 1.04

1.09 1.22 1.16 1.09 0.86 0.94 1.00 0.83 0.69 1.09

(1.06–1.23) (0.79–1.43) (0.85–0.96) (0.87–0.97) (0.86–1.03) (0.85–0.92) (0.92–1.28) (0.85–1.23) (0.57–0.78) (1.21–1.43)

(0.94–1.11) (0.85–1.56) (0.94–1.09) (0.93–1.04) (0.88–1.08) (0.96–1.06) (1.29–1.83) (0.59–0.89) (0.71–1.05) (1.34–1.58)

(0.88–1.01) (1.01–1.72) (1.05–1.18) (1.06–1.17) (0.82–0.98) (0.92–1.00) (0.94–1.30) (0.81–1.11) (0.67–0.92) (0.96–1.12)

(1.02–1.17) (0.94–1.59) (1.09–1.23) (1.04–1.14) (0.79–0.94) (0.91–0.98) (0.85–1.17) (0.71–0.98) (0.59–0.81) (1.01–1.17)

1 2.17 (2.08–2.26) 3.62 (3.09–4.24)

1 1.20 (1.14–1.26) 1.45 (1.29–1.62)

1 1.13 (1.08–1.17) 1.62 (1.46–1.81)

1 0.94 (0.91–0.98) 1.22 (1.10–1.36)

1 1.25 (1.19–1.31) 1.69 (1.60–1.78)

1 1.14 (1.04–1.26) 1.40 (1.27–1.55)

1 0.98 (0.92–1.05) 1.15 (1.07–1.23)

1 1.00 (0.95–1.07) 1.17 (1.10–1.25)

1 4.78 (4.50–5.07) 12.88 (12.11–13.71) 38.56 (35.66–41.69)

1 5.14 (4.37–6.06) 14.87 (12.65–17.49) 37.15 (31.42–43.91)

1 4.91 (4.45–5.42) 14.50 (13.15–16.00) 43.27 (38.95–48.07)

1 4.03 (3.71–4.38) 11.77 (10.84–12.78) 38.67 (35.30–42.37)





TABLE 4 (Continued) Characteristic GI surgery No Yes IBD medication use Oral steroid 5-Aminosalicylic acid drugs Azathioprine/6-MP Rectal steroid Methotrexate Cyclosporine or tacrolimus Biologics

Narcotic Analgesics

Nonnarcotic Analgesics

Anxiolytics/Sedatives/Hypnotics

Antidepressants

1 2.15 (2.00–2.32)

1 1.01 (0.94–1.09)

1 0.98 (0.92–1.04)

1 0.93 (0.87–0.99)

1.03 0.71 0.81 0.75 0.76 0.61 1.00

1.05 0.87 0.86 0.76 1.00 0.57 0.94

0.95 0.78 0.82 0.96 0.73 0.79 0.94

0.77 0.79 0.91 0.77 0.85 0.60 0.91

(1.00–1.07) (0.68–0.73) (0.79–0.84) (0.67–0.84) (0.69–0.85) (0.49–0.75) (0.96–1.05)

(1.01–1.10) (0.83–0.91) (0.82–0.90) (0.65–0.89) (0.90–1.12) (0.45–0.74) (0.89–1.00)

(0.91–0.98) (0.75–0.81) (0.79–0.85) (0.85–1.08) (0.66–0.81) (0.65–0.96) (0.90–0.98)

(0.75–0.80) (0.76–0.82) (0.87–0.94) (0.68–0.87) (0.77–0.94) (0.49–0.73) (0.87–0.96)

a PORs and 95% CIs are adjusted for all other predictors listed in the table and were estimated in a separate multivariable model for each drug class. CI, confidence interval.

dispensings for analgesic and psychiatric medications are of particular interest. We observed reduced use of these drugs among those taking 5-aminosalicylic acid, azothioprine/6-MP, rectal steroids, methotrexate, and cyclosporine or tacrolimus. Since analgesic and psychiatric disorders correlate with disease activity, these findings indirectly suggest that effective IBD treatment may reduce the need for these medications. The contrasting null association between oral steroids and biologics with the use of psychiatric medications may be related to their use in more severe IBD. In addition, steroids are used primarily to treat acute flares and have been associated with psychiatric symptoms in the general population and among individuals with IBD.7 A methodological implication of the relationship between analgesic and psychiatric medication use and active disease is that these medications might be used as surrogates for well being and quality of life in clinical effectiveness and comparative effectiveness studies of IBD using administrative data. Quality of life indicators are important measures for comparative effectiveness research but useful markers are difficult to identify using administrative claims data. Although administrative claims data are routinely used in pharmacoepidemiology studies, this analysis is subject to several limitations inherent to analyses of claims data. Measurement of prescription drug use is susceptible to misclassification. It is unknown whether a dispensed drug was actually taken or if it was prescribed for the labeled indication. Our data characterized prescriptions dispensed to the patient, reducing the likelihood of misclassification compared with information on prescribed medications only. Lack of data on nonprescription medication use is a limitation of claims data that is particularly relevant to our analysis of nonnarcotic analgesics, many of which are over-the-counter. Although over-the-counter medications are important to the overall disease burden for IBD, prescription medications are indicative of more severe health states requiring treatment. Disease misclassification may have occurred if

individuals with mild IBD did not have healthcare contacts during the study period causing them to be classified as disease-free or if individuals were misclassified as having IBD due to claims for diagnostic testing despite not ultimately receiving a diagnosis. Lifestyle characteristics that may differ by disease status, such as smoking, body mass index, and social support, are not captured in administrative claims data and could not be assessed as predictors of prescription drug dispensings. Similarly, we could not assess clinical markers such as disease activity, severity, or health-related quality of life. This descriptive, cross-sectional study provides information on the prevalence of dispensed prescription medications among patients with IBD, an important aspect of the disease burden that has not previously been described. Prospective studies are needed to assess whether patients with IBD are at increased risk of the conditions for which medications are prescribed. In conclusion, our findings demonstrate that patients with IBD have increased use of prescription medications. IBD providers should be aware of polypharmacy and its potential for drug interactions. The high burden of analgesic and psychiatric drug use is of particular concern, and associations between use of these drugs and increased healthcare utilization indicate that they may be useful surrogates for well being and quality of life in studies using administrative claims data.

REFERENCES 1. Cohen RD. The quality of life in patients with Crohn’s disease. Aliment Pharmacol Ther. 2002;16:1603–1609. 2. Ferguson A, Sedgwick DM, Drummond J. Morbidity of juvenile onset inflammatory bowel disease: effects on education and employment in early adult life. Gut. 1994;35:665–668. 3. Longobardi T, Jacobs P, Bernstein CN. Work losses related to inflammatory bowel disease in the United States: results from the National Health Interview Survey. Am J Gastroenterol. 2003;98:1064–1072. 4. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004; 126:1504–1517. www.ibdjournal.org |

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APPENDIX: Generic Compound Names of Medications Included in Each A Priori Drug Class Narcotic analgesics

Acetaminophen Acetaminophen, Butalbital, Codeine, Caffeine Acetaminophen, Caffeine, Butalbital, Codeine Acetaminophen, Caffeine, Dihydrocodeine Acetaminophen, Codeine Acetaminophen, Dihydrocodeine, Caffeine Acetaminophen, Hydrocodone Acetaminophen, Oxycodone Acetaminophen, Pentazocine Acetaminophen, Phenyltoloxamine Acetaminophen, Propoxyphene Acetylsalicylic acid, Butalbital, Caffeine, Codeine Acetylsalicylic acid, Butalbital, Codeine, Caffeine Acetylsalicylic acid, Codeine Acetylsalicylic acid, Hydrocodone Acetylsalicylic acid, Oxycodone Acetylsalicylic acid, Oxycodone, Oxycodone Buprenorphine Butalbital, Acetaminophen, Caffeine, Codeine Butalbital, Acetylsalicylic acid, Caffeine, Codeine Butalbital, Codeine, Caffeine, Acetaminophen Butorphanol Caffeine, Acetylsalicylic acid, Butalbital Caffeine, Acetylsalicylic acid, Butalbital, Codeine Caffeine, Acetylsalicylic acid, Dihydrocodeine Caffeine, Acetylsalicylic acid, Propoxyphene Caffeine, Ergotamine, Belladonna, Pentobarbital Codeine Codeine, Acetaminophen Codeine, Acetaminophen, Caffeine, Butalbital Codeine, Acetylsalicylic acid Codeine, Acetylsalicylic acid, Butalbital, Caffeine




Dihydrocodeine, Acetaminophen, Caffeine Dihydrocodeine, Acetylsalicylic acid, Caffeine Fentanyl Homatropine, Hydrocodone Hydrocodone, Acetaminophen Hydrocodone, Acetaminophen, Choline, 4-Aminobutyric acid, Vine, Theobromine Hydrocodone, Acetaminophen, Herbal Hydrocodone, Acetylsalicylic acid Hydrocodone, Ibuprofen Hydromorphone Ibuprofen, Hydrocodone Levorphanol Meperidide Meperidine Meperidine, Promethazine Meperidine, Sodium Methadone Morphine Morphine, Naltrexone Naloxone, Pentazocine Opium Oxycodone Oxycodone, Acetaminophen Oxycodone, Acetylsalicylic acid Oxycodone, Ibuprofen Oxycodone, Oxycodone, Acetylsalicylic acid Oxymorphone Pentazocine Pentazocine, Naloxone Propoxyphene Propoxyphene, Acetaminophen Propoxyphene, Acetylsalicylic acid, Caffeine Propoxyphene, Caffeine, Acetylsalicylic acid Tapentadol Nonnarcotic analgesics

Acetaminophen Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen, Acetaminophen,

Acetylsalicylic acid Acetylsalicylic acid, Caffeine Butabarbital Butalbital Butalbital, Caffeine Caffeine Caffeine, Acetylsalicylic acid Caffeine, Butabarbital Caffeine, Butalbital Caffeine, Phenyltoloxamine, Salicylamide Caffeine, Pyrilamine Dichloralphenazone, Isometheptene Diphenhydramine Hydrocodone Magnesium, Caffeine, Phenyltoloxamine


Acetaminophen, Pamabrom Acetaminophen, Phenyltoloxamine Acetaminophen, Phenyltoloxamine, Salicylamide Acetaminophen, Pyrilamine Acetaminophen, Pyrilamine, Caffeine Acetaminophen, Salicylamide, Caffeine, Phenyltoloxamine Acetaminophen, Salicylamide, Phenyltoloxamine Acetylsalicylic acid Acetylsalicylic acid, Acetaminophen, Caffeine Acetylsalicylic acid, Aluminum, Magnesium Acetylsalicylic acid, Aluminum and Magnesium Acetylsalicylic acid, Butalbital, Caffeine Acetylsalicylic acid, Caffeine Acetylsalicylic acid, Caffeine, Butalbital Acetylsalicylic acid, Calcium, Magnesium, Aluminum Acetylsalicylic acid, Calcium, Magnesium, Magnesium Acetylsalicylic acid, Citric acid, Sodium Acetylsalicylic acid, Dihydroxyaluminium, Magnesium Acetylsalicylic acid, Magnesium, Calcium Acetylsalicylic acid, Meprobamate Acetylsalicylic acid, Pentazocine Acetylsalicylic acid, Phenyltoloxamine Acetylsalicylic acid, Salicylamide, Acetaminophen, Caffeine Acetylsalicylic acid, Sodium, Citric acid Analgesic (Pain) Bromfenac Buprenorphine Butalbital, Acetaminophen Butalbital, Acetaminophen, Caffeine Butalbital, Acetylsalicylic acid, Caffeine Caffeine, Acetaminophen, Butalbital Caffeine, Acetylsalicylic acid Caffeine, Acetylsalicylic acid, Acetaminophen Caffeine, Acetylsalicylic acid, Butalbital Caffeine, Acetylsalicylic acid, Butalbital, Codeine Caffeine, Acetylsalicylic acid, Phenacetin, Butalbital Caffeine, Butalbital, Acetaminophen Chlorzoxazone, Acetaminophen Chlorzoxazone, Acetaminophen, Phenyltoloxamine Choline, Magnesium Citric acid, Acetaminophen, Sodium Citric acid, Acetylsalicylic acid, Sodium Citric acid, Sodium, Acetylsalicylic acid Clonidine Diclofenac Diflunisal Dimethylsulfone Diphenhydramine, Acetaminophen Diphenhydramine, Ibuprofen Fenoprofen Ibuprofen Ibuprofen, Diphenhydramine Ketoprofen

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Ketorolac Magnesium Magnesium, Acetaminophen, Caffeine, Phenyltoloxamine Magnesium, Phenyltoloxamine Mefenamic acid Nalbuphine Naloxone, Pentazocine Naproxen Pentazocine Pentazocine, Acetaminophen Pentazocine, Naloxone Phenyltoloxamine, Acetaminophen Phenyltoloxamine, Magnesium Pseudoephedrine, Ibuprofen Salicil Salicylamide Salicylamide, Acetaminophen Salicylamide, Acetaminophen, Phenyltoloxamine Salicylamide, Acetaminophen, Phenyltoloxamine, Caffeine Salicylamide, Caffeine, Acetylsalicylic acid Salicylamide, Mephenesin, Butabarbital Salicylic acid Salicylic acid, Diphenhydramine Salsalate Sodium Tramadol Tramadol, Acetaminophen Tramadol, Glucosamine Tramadol, Herbal, Aminoacids Ziconotide Anxiolytics/sedatives/hypnotics

Acetaminophen, Diphenhydramine Alprazolam Alprazolam, Herbal Antihistamines Bupropion Buspirone Chloral Hydrate Chlordiazepoxide Clomipramine Clorazepate Diazepam Diphenhydramine Doxepin Doxylamine Estazolam Eszopiclone Ethchlorvynol Flurazepam Glutethimide

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Halazepam Homeopathic medicine Lorazepam Meprobamate Midazolam Oxazepam Quazepam Ramelteon Temazepam Temazepam, Aminoacids, Herbal Triazolam Zaleplon Zolpidem Zolpidem, Herbal Antidepressants

Amitriptyline Amitriptyline, Chlordiazepoxide Amitriptyline, Perphenazine Amoxapine Bupropion Bupropion, Herbal Chlordiazepoxide, Amitriptyline Citalopram Desipramine Desvenlafaxine Doxepin Duloxetine Escitalopram Fluoxetine Fluoxetine, Herbal Fluvoxamine Imipramine Isocarboxazid Maprotiline Mirtazapine Nefazodone Nortriptyline Olanzapine, Fluoxetine Paroxetine Perphenazine, Amitriptyline Phenelzine Protriptyline Selegiline Sertraline Tranylcypromine Trazodone Trazodone, Herbal, Aminoacids Trimipramine Venlafaxine Vilazodone



Pivot to Asia: inflammatory bowel disease burden.

Marijuana use patterns among patients with inflammatory bowel disease.

A 'cocoon immunization strategy' among patients with inflammatory bowel disease.

Vaccination of Patients With Inflammatory Bowel Disease.

Assessment of sexual function among inflammatory bowel disease patients.

Beliefs and behaviour about smoking among inflammatory bowel disease patients.

Prevalence of inflammatory bowel disease among relatives of patients with Crohn's disease.

Perspectives and attitudes of young patients with inflammatory bowel disease: symptoms, burden of disease and communication with their healthcare professionals.

Does the level of reproductive knowledge specific to inflammatory bowel disease predict childlessness among women with inflammatory bowel disease?

The increasing incidence of thromboembolic events among hospitalized patients with inflammatory bowel disease.

Inflammatory bowel disease among college students.

Persistent Reactive Thrombocytosis May Increase the Risk of Coronary Artery Disease Among Inflammatory Bowel Disease Patients.

Increased incidence of critical illness among patients with inflammatory bowel disease: a population-based study.

Frequency and associated factors of hair loss among patients with inflammatory bowel disease.

Alexithymia and personality traits of patients with inflammatory bowel disease.

Prevalence of Anal Dysplasia in Patients With Inflammatory Bowel Disease.

Sense of coherence in patients with inflammatory bowel disease.

Combined Immunosuppression Impairs Immunogenicity to Tetanus and Pertussis Vaccination Among Patients with Inflammatory Bowel Disease.

Immunization rates and vaccine beliefs among patients with inflammatory bowel disease: an opportunity for improvement.

Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study.

Pyoderma Gangrenosum among Patients with Inflammatory Bowel Disease: A Descriptive Cohort Study.

Prevalence of inflammatory bowel disease among coeliac disease patients in a Hungarian coeliac centre.

Disability and need for rehabilitation among patients with inflammatory bowel disease.

Inflammatory bowel disease in liver transplanted patients.